Crystalline forms of [R-(R*,R*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1)

ABSTRACT

Novel crystalline forms of [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid hemi calcium salt designated Form V, Form VI, Form VII, Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII, Form XIV, Form XV, Form XVI, Form XVII, Form XVIII, and Form XIX are characterized by their X-ray powder diffraction, solid-state NMR, and/or Raman spectroscopy are described, as well as methods for the preparation and pharmaceutical composition of the same, which are useful as agents for treating hyperlipidemia, hypercholesterolemia, osteoporosis, and Alzheimer&#39;s disease.

FIELD OF THE INVENTION

[0001] The present invention relates to novel crystalline forms ofatorvastatin which is known by the chemical name[R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid hemi calcium salt useful as pharmaceutical agents, to methods fortheir production and isolation, to pharmaceutical compositions whichinclude these compounds and a pharmaceutically acceptable carrier, aswell as methods of using such compositions to treat subjects, includinghuman subjects, suffering from hyperlipidemia, hypercholesterolemia,osteoporosis, and Alzheimer's disease.

BACKGROUND OF THE INVENTION

[0002] The conversion of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)to mevalonate is an early and rate-limiting step in the cholesterolbiosynthetic pathway. This step is catalyzed by the enzyme HMG-CoAreductase. Statins inhibit HMG-CoA reductase from catalyzing thisconversion. As such, statins are collectively potent lipid loweringagents.

[0003] Atorvastatin calcium, disclosed in U.S. Pat. No. 5,273,995, whichis incorporated herein by reference, is currently sold as Lipitor®having the chemical name[R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid calcium salt (2:1) trihydrate and the formula

[0004] Atorvastatin calcium is a selective, competitive inhibitor ofHMG-CoA reductase. As such, atorvastatin calcium is a potent lipidlowering compound and is thus useful as a hypolipidemic and/orhypocholesterolemic agent.

[0005] U.S. Pat. No. 4,681,893, which is incorporated herein byreference, discloses certain trans-6-[2-(3- or4-carboxamido-substituted-pyrrol-1-yl)alkyl]-4-hydroxy-pyran-2-onesincluding trans (±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[(2-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide.

[0006] U.S. Pat. No. 5,273,995, which is herein incorporated byreference, discloses the enantiomer having the R form of the ring-openedacid of trans-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[(2-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide,ie,[R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)-carbonyl]-1H-pyrrole-1-heptanoicacid which is atorvastatin.

[0007] U.S. Pat. Nos. 5,003,080; 5,097,045; 5,103,024; 5,124,482;5,149,837; 5,155,251; 5,216,174; 5,245,047; 5,248,793; 5,280,126;5,397,792; 5,342,952; 5,298,627; 5,446,054; 5,470,981; 5,489,690;5,489,691; 5,510,488; 5,998,633; and 6,087,511, which are hereinincorporated by reference, disclose various processes and keyintermediates for preparing amorphous atorvastatin. Amorphousatorvastatin has unsuitable filtration and drying characteristics forlarge-scale production and must be protected from heat, light, oxygen,and moisture.

[0008] Crystalline forms of atorvastatin calcium are disclosed in U.S.Pat. Nos. 5,969,156 and 6,121,461 which are herein incorporated byreference.

[0009] International Published Patent Application Number WO 01/36384allegedly discloses a polymorphic form of atorvastatin calcium.

[0010] Stable oral formulations of atorvastatin calcium are disclosed inU.S. Pat. Nos. 5,686,104 and 6,126,971.

[0011] Atorvastatin is prepared as its calcium salt, ie,[R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid calcium salt (2:1). The calcium salt is desirable since it enablesatorvastatin to be conveniently formulated in, for example, tablets,capsules, lozenges, powders, and the like for oral administration.Additionally, there is a need to produce atorvastatin in a pure andcrystalline form to enable formulations to meet exacting pharmaceuticalrequirements and specifications.

[0012] Furthermore, the process by which atorvastatin is produced needsto be one which is amenable to large-scale production. Additionally, itis desirable that the product should be in a form that is readilyfilterable and easily dried. Finally, it is economically desirable thatthe product be stable for extended periods of time without the need forspecialized storage conditions.

[0013] We have now surprisingly and unexpectedly found novel crystallineforms of atorvastatin. Thus, the present invention provides atorvastatinin new crystalline forms designated Forms V, VI, VII, VIII, IX, X, XI,XII, XIII, XIV, XV, XVI, XVII, XVIII, and XIX. The new crystalline formsof atorvastatin are purer, more stable, or have advantageousmanufacturing properties than the amorphous product.

SUMMARY OF THE INVENTION

[0014] Accordingly, the present invention is directed to crystallineForm V atorvastatin and hydrates thereof characterized by the followingX-ray powder diffraction pattern expressed in terms of the 2θ andrelative intensities with a relative intensity of >10% measured on aShimadzu diffractometer with CuK_(α) radiation: Relative Intensity 2θ(>10%)^(a) 4.9 (broad) 9  6.0 15  7.0 100 8.0 (broad) 20  8.6 57  9.9 2216.6 42 19.0 27 21.1 35

[0015] Additionally, the following X-ray powder diffraction pattern ofcrystalline Form V atorvastatin expressed in terms of the 2θ values wasmeasured on an Inel (capillary) diffractometer: 2θ  5.0  6.1  7.5 8.4(broad) 8.7 (broad)  9.9 16.7 19.0 21.2

[0016] Further, the present invention is directed to crystalline Form Vatorvastatin and hydrates thereof characterized by the followingsolid-state ¹³C nuclear magnetic resonance (ssNMR) spectrum whereinchemical shift is expressed in parts per million: Assignment ChemicalShift C12 or C25 185.7 C12 or C25 176.8 C16 166.9 Aromatic Carbons 138.7C2-C5, C13-C18, 136.3 C19-C24, C27-C32 133.0 128.4 122.0 117.0 116.3 C8,C10 68.0 Methylene Carbons 43.1 C6, C7, C9, C11 C33 25.6 C34 19.9

[0017] Additionally, the present invention is directed to crystallineForm V atorvastatin and hydrates thereof characterized by the followingRaman spectrum having peaks expressed in cm⁻¹: 3062 1652 1604 1528 14781440 1413 1397 1368 1158 1034 1001 825 245 224 130

[0018] In a preferred embodiment of the first aspect of the invention,crystalline Form V atorvastatin is a trihydrate.

[0019] In a second aspect, the present invention is directed tocrystalline Form VI atorvastatin and hydrates thereof characterized bythe following X-ray powder diffraction pattern expressed in terms of the2θ and relative intensities with a relative intensity of >10% measuredon a Shimadzu diffractometer with CuK_(α) radiation: Relative Intensity2θ (>10%)^(a)  7.2 11  8.3 77 11.0 20 12.4 11 13.8 9 16.8 14 18.5 100 19.7 (broad) 22 20.9 14 25.0 (broad) 15

[0020] Additionally, the following X-ray powder diffraction pattern ofcrystalline Form VI atorvastatin expressed in terms of the 2θ values wasmeasured on an Inel (capillary) diffractometer: 2θ  7.3  8.5 11.2 12.714.0 17.1 (broad) 18.7 19.9 21.1 (broad) 25.2 (broad)

[0021] Further, the present invention is directed to crystalline Form VIatorvastatin and hydrates thereof characterized by the followingsolid-state ¹³C nuclear magnetic resonance spectrum wherein chemicalshift is expressed in parts per million: Assignment Chemical Shift C12or C25 176.5 C16 or C12 or C25 168.2 C16 or C12 or C25 163.1 C16 or C12or C25 159.8 Aromatic Carbons 136.8 C2-C5, C13-C18, 127.8 C19-C24,C27-C32 122.3 118.8 113.7 C8, C10 88.2 C8, C10 79.3 70.5 MethyleneCarbons 43.3 C6, C7, C9, C11 36.9 31.9 C33, C34 25.9 C33, C34 22.5

[0022] In a third aspect, the present invention is directed tocrystalline Form VII atorvastatin and hydrates thereof characterized bythe following X-ray powder diffraction pattern expressed in terms of the2θ and relative intensities with a relative intensity of >10% measuredon a Shimadzu diffractometer with CuK_(α) radiation: Relative Intensity2θ (>10%)  8.6 76 10.2 70 12.4 (broad) 12 12.8 (broad) 15 17.6 20 18.3(broad) 43 19.3 100  22.2 (broad) 14 23.4 (broad) 23 23.8 (broad) 2625.5 (broad) 16

[0023] Additionally, the following X-ray powder diffraction pattern ofcrystalline Form VII atorvastatin expressed in terms of the 2θ valueswas measured on an Inel (capillary) diffractometer: 2θ  8.7 10.2 12.412.9 17.6 18.4 19.4 22.2 23.5 23.9 25.6

[0024] Further, the present invention is directed to crystalline FormVII atorvastatin and hydrates thereof characterized by the followingsolid-state ¹³C nuclear magnetic resonance spectrum wherein chemicalshift is expressed in parts per million: Assignment Chemical Shift C12or C25 186.5 C12 or C25 183.3 C12 or C25 176.8 C16 166.5 159.2 AromaticCarbons 137.6 C2-C5, C13-C18, 128.3 C19-C24, C27-C32 122.3 119.2 C8, C1074.5 C8, C10 70.3 C8, C10 68.3 C8, C10 66.2 Methylene Carbons 43.5 C6,C7, C9, C11 40.3 C33, C34 26.3 C33, C34 24.9 C33, C34 20.2

[0025] Additionally, the present invention is directed to crystallineForm VII atorvastatin and hydrates thereof characterized by thefollowing Raman spectrum having peaks expressed in cm⁻¹: Raman Spectrum3060 2927 1649 1603 1524 1476 1412 1397 1368 1159 1034 998 824 114

[0026] In a preferred embodiment of the third aspect of the invention,crystalline Form VII atorvastatin is a sesquihydrate.

[0027] In a fourth aspect, the present invention is directed tocrystalline Form VIII atorvastatin and hydrates thereof characterized bythe following X-ray powder diffraction pattern expressed in terms of the2θ and relative intensities with a relative intensity of >10% measuredon a Shimadzu diffractometer with CuK_(α) radiation: Relative Intensity2θ (>10%)^(a)  7.5 61  9.2 29 10.0 16 12.1 10 12.8 6 13.8 4 15.1 13 16.7(broad) 64 18.6 (broad) 100 20.3 (broad) 79 21.2 24 21.9 30 22.4 19 25.833 26.5 20 27.4 (broad) 38 30.5 20

[0028] Additionally, the following X-ray powder diffraction pattern ofcrystalline Form VIII atorvastatin expressed in terms of the 2θ valueswas measured on an Inel (capillary) diffractometer: 2θ  7.5  9.3 10.112.2 12.8 13.8 15.1 16.6-16.9 18.5-18.9 20.2-20.6 21.3 22.0 22.5 25.926.5 27.4 (broad) 30.6

[0029] Further, the present invention is directed to crystalline FormVIII atorvastatin and hydrates thereof characterized by the followingsolid-state ¹³C nuclear magnetic resonance spectrum wherein chemicalshift is expressed in parts per million: Assignment Chemical Shift C12or C25 186.1 C12 or C25 179.5 C16 167.9 C16 161.0 Aromatic Carbons 139.4C2-C5, C13-C18, 132.9 C19-C24, C27-C32 128.7 124.7 121.8 116.6 C8, C1067.0 Methylene Carbons 43.3 C6, C7, C9, C11 C33, C34 26.7 C33, C34 24.7C33, C34 20.9 C33, C34 20.1

[0030] Additionally, the present invention is directed to crystallineForm VIII atorvastatin and hydrates thereof characterized by thefollowing Raman spectrum having peaks expressed in cm⁻¹: Raman Spectrum3065 2923 1658 1603 1531 1510 1481 1413 997 121

[0031] In a preferred embodiment of the fourth aspect of the invention,crystalline Form VIII atorvastatin is a dihydrate.

[0032] In a fifth aspect, the present invention is directed tocrystalline Form IX atorvastatin and hydrates thereof characterized bythe following X-ray powder diffraction pattern expressed in terms of the2θ and relative intensities with a relative intensity of >10% measuredon a Shimadzu diffractometer with CuK_(α) radiation: Relative Intensity2θ (>10%)  8.8 50  9.4 (broad) 32 11.2-11.7 (broad) 26 16.7 59 17.5(broad) 33 19.3 (broad) 55 21.4 (broad) 100 22.4 (broad) 33 23.2 (broad)63 29.0 (broad) 15

[0033] Additionally, the following X-ray powder diffraction pattern ofcrystalline Form IX atorvastatin expressed in terms of the 2θ values wasmeasured on an Inel (capillary) diffractometer: 2θ  9.0  9.4 10.0-10.5(broad) 11.8-12.0 (broad) 16.9 17.5 (broad) 19.4 (broad) 21.6 (broad)22.6 (broad) 23.2 (broad) 29.4 (broad)

[0034] In a sixth aspect, the present invention is directed tocrystalline Form X atorvastatin and hydrates thereof characterized bythe following X-ray powder diffraction pattern expressed in terms of the2θ and relative intensities with a relative intensity of >10% measuredon a Shimadzu diffractometer with CuK_(α) radiation: Relative Intensity2θ (>10%)  4.7 35  5.2 24  5.8 11  6.9 13  7.9 53  9.2 56  9.5 50 10.3(broad) 13 11.8 20 16.1 13 16.9 39 19.1 100  19.8 71 21.4 49 22.3(broad) 36 23.7 (broad) 37 24.4 15 28.7 31

[0035] Additionally, the following X-ray powder diffraction pattern ofcrystalline Form X atorvastatin expressed in terms of the 2θ values wasmeasured on an Inel (capillary) diffractometer: 2θ  4.7  5.2  5.8  6.9 7.9  9.2  9.6 10.2-10.4 11.9 16.2 16.9 19.1 19.9 21.5 22.3-22.623.7-24.0 (broad) 24.5 28.8

[0036] Further, the present invention is directed to crystalline Form Xatorvastatin and hydrates thereof characterized by the followingsolid-state ¹³C nuclear magnetic resonance spectrum wherein chemicalshift is expressed in parts per million: Assignment Chemical Shift C12or C25 187.0 C12 or C25 179.5 C16 165.5 C16 159.4 Aromatic Carbons 137.9C2-C5, C13-C18, 134.8 C19-C24, C27-C32 129.4 127.9 123.2 119.9 C8, C1071.1 Methylene Carbons 43.7 C6, C7, C9, C11 40.9 C33 26.4 25.3 C34 20.318.3

[0037] Additionally, the present invention is directed crystalline FormX atorvastatin and hydrates thereof characterized by the following Ramanspectrum having peaks expressed in cm⁻¹: Raman Spectrum 3062 2911 16501603 1525 1478 1411 1369 1240 1158 1034 999 824 116

[0038] In a preferred embodiment of the sixth aspect of the invention,crystalline Form X atorvastatin is a trihydrate.

[0039] In a seventh aspect, the present invention is directed tocrystalline Form XI atorvastatin and hydrates thereof characterized bythe following X-ray powder diffraction pattern expressed in terms of the2θ and relative intensities with a relative intensity of >10% measuredon a Shimadzu diffractometer with CuK_(α) radiation: Relative Intensity2θ (>10%) 10.8 (broad) 58 12.0 12 13.5 11 16.5 52 17.6-18.0 (broad) 3519.7 82 22.3 100  23.2 26 24.4 28 25.8 17 26.5 30 27.3 31 28.7 19 29.512 30.9 (broad) 17 32.8 (broad) 11 33.6 (broad) 15 36.0 (broad) 15 38.5(broad) 14

[0040] In an eighth aspect, the present invention is directed tocrystalline Form XII atorvastatin and hydrates thereof characterized bythe following X-ray powder diffraction pattern expressed in terms of the2θ and relative intensities with a relative intensity of >10% measuredon a Shimadzu diffractometer with CuK_(α) radiation: Relative Intensity2θ (>10%)^(a)  5.4 11  7.7 24  8.0 25  8.6 42  8.9 25  9.9 36 10.4(broad) 24 12.5 18 13.9 (broad) 9 16.2 10 17.8 70 19.4 100 20.8 51 21.713 22.4-22.6 (broad) 18 24.3 19 25.5 24 26.2 11 27.1 8

[0041] Additionally, the following X-ray powder diffraction pattern ofcrystalline Form XII atorvastatin expressed in terms of the 2θ valueswas measured on an Inel (capillary) diffractometer: 2θ  5.4  7.7  8.1 8.6  8.9 10.0 10.5 12.6 14.0 (broad) 16.2 17.9 19.4 20.9 21.8 22.5-22.8(broad) 24.4 25.6 26.4 27.2

[0042] Additionally, the present invention is directed crystalline FormXII atorvastatin and hydrates thereof characterized by the followingRaman spectrum having peaks expressed in cm⁻¹: Raman Spectrum 3064 29732926 1652 1603 1527 1470 1410 1367 1240 1159 1034 1002  823

[0043] In a ninth aspect, the present invention is directed tocrystalline Form XIII atorvastatin and hydrates thereof characterized bythe following X-ray powder diffraction pattern expressed in terms of the2θ and relative intensities with a relative intensity of >10% measuredon a Shimadzu diffractometer with CuK_(α) radiation: Relative Intensity2θ (>10%) 8.4 100  8.9 82 15.7 (broad) 45 16.4 (broad) 46 17.6 (broad)57 18.1 (broad) 62 19.7 (broad) 58 20.8 (broad) 91 23.8 (broad  57

[0044] In a tenth aspect, the present invention is directed tocrystalline Form XIV atorvastatin and hydrates thereof characterized bythe following X-ray powder diffraction pattern expressed in terms of the2θ and relative intensities with a relative intensity of >10% measuredon a Bruker D5000 diffractometer with CuK_(α) radiation: RelativeIntensity 2θ (>10%) 5.4 41 6.7 31 7.7 100  8.1 35 9.0 65 16.5 (broad) 1517.6 (broad) 17 18.0-18.7 (broad) 21 19.5 (broad) 18

[0045] In an eleventh aspect, the present invention is directed tocrystalline Form XV atorvastatin and hydrates thereof characterized bythe following X-ray powder diffraction pattern expressed in terms of the2θ and relative intensities with a relative intensity of >10% measuredon a Bruker D5000 diffractometer with CuKα radiation: Relative Intensity2θ (>10%) 5.7 26 6.1 21 6.8 18 7.5 39 8.1 39 8.5 42 9.5 33 10.5 (broad)18 19.1-19.6 (broad) 32

[0046] In a twelfth aspect, the present invention is directed tocrystalline Form XVI atorvastatin and hydrates thereof characterized bythe following X-ray powder diffraction pattern expressed in terms of the2θ and relative intensities with a relative intensity of >10% measuredon a Bruker D5000 diffractometer with CuK_(α) radiation: RelativeIntensity 2θ (>10%) 5.2 37 6.4 34 7.5 100  8.7 79 10.5 (broad) 19 12.0(broad) 10 12.7 (broad) 17 16.7  26 18.3 (broad) 27 19.5  23 20.1-20.4(broad) 37 21.2-21.9 (broad) 32 22.9-23.3 (broad) 38 24.4-25.0 (broad)35

[0047] Additionally, the following X-ray powder diffraction pattern ofcrystalline Form XVI atorvastatin expressed in terms of the 2θ valueswas measured on a Shimadzu diffractometer with CuK_(α) radiation: 2θ 7.68.8 10.2 12.5 16.8 18.2 19.3 20.5 23.0 24.8

[0048] In addition, the following X-ray powder diffraction pattern ofcrystalline Form XVI atorvastatin expressed in terms of the 2θ valueswas measured on an Inel (capillary) diffractometer: 2θ  5.1  6.2  7.3 8.7 10.2 (broad) 12.0 (broad) 12.7 (broad) 16.7 18.0 (broad) 19.5(broad) 20.0-20.5 (broad) 21.5-21.6 (broad) 22.9-23.3 (broad) 24.0-25.0(broad)

[0049] In a thirteenth aspect, the present invention is directed tocrystalline Form XVII atorvastatin and hydrates thereof characterized bythe following X-ray powder diffraction pattern expressed in terms of the2θ and relative intensities with a relative intensity of >10% measuredon a Bruker D5000 diffractometer with CuK_(α) radiation: RelativeIntensity 2θ (>10%)  5.0 27  6.1 33  7.3 100   7.9 30  8.5 29  9.1 2210.0 45 12.1 (broad) 24 14.8 17 16.0-16.5 (broad) 20 17.5 (broad) 2819.0 (broad) 46 19.5 65 20.2 (broad) 47 21.3 64 21.6 55 22.0 45

[0050] In a fourteenth aspect, the present invention is directed tocrystalline Form XVIII atorvastatin and hydrates thereof characterizedby the following X-ray powder diffraction pattern expressed in terms ofthe 2θ and relative intensities with a relative intensity of >10%measured on a Bruker D5000 diffractometer with CuK_(α) radiation:Relative Intensity 2θ (>10%)  8.0 100   9.2 (broad) 52  9.7 (broad) 4012.1 24 16.6 (broad) 48 18.5 67

[0051] Additionally, the following X-ray powder diffraction pattern ofcrystalline Form XVIII atorvastatin expressed in terms of the 2θ valueswas measured on a Shimadzu diffractometer with CuK_(α) radiation: 2θ 7.79.3 9.9 12.2 16.8 18.5

[0052] In addition, the following X-ray powder diffraction pattern ofcrystalline Form XVIII atorvastatin expressed in terms of the 2θ valueswas measured on an Inel (capillary) diffractometer: 2θ  7.9  9.2 (broad) 9.8 (broad) 12.2 (broad) 16.7 (broad) 18.5

[0053] In a fifteenth aspect, the present invention is directed tocrystalline Form XIX atorvastatin and hydrates thereof characterized bythe following X-ray powder diffraction pattern expressed in terms of the2θ and relative intensities with a relative intensity of >10% measuredon a Bruker D5000 diffractometer with CuK_(α) radiation: RelativeIntensity 2θ (>10%)  5.2 32  6.3 28  7.0 100   8.6 74 10.5 34 11.6(broad) 26 12.7 (broad) 35 14.0 15 16.7 (broad) 30 18.9 86 20.8 94 23.6(broad) 38 25.5 (broad) 32

[0054] As inhibitors of HMG-CoA reductase, the novel crystalline formsof atorvastatin are useful hypolipidemic and hypocholesterolemic agentsas well as agents in the treatment of osteoporosis and Alzheimer'sdisease.

[0055] A still further embodiment of the present invention is apharmaceutical composition for administering an effective amount ofcrystalline Form V, Form VI, Form VII, Form VIII, Form IX, Form X, FormXI, Form XII, Form XIII, Form XIV, Form XV, Form XVI, Form XVII, FormXVIII, or Form XIX atorvastatin in unit dosage form in the treatmentmethods mentioned above. Finally, the present invention is directed tomethods for production of Form V, Form VI, Form VII, Form VIII, Form IX,Form X, Form XI, Form XII, Form XIII, Form XIV, Form XV, Form XVI, FormXVII, Form XVIII, or Form XIX atorvastatin.

BRIEF DESCRIPTION OF THE DRAWINGS

[0056] The invention is further described by the following nonlimitingexamples which refer to the accompanying FIGS. 1 to 35, shortparticulars of which are given below.

[0057]FIG. 1

[0058] Diffractogram of Form V atorvastatin carried out on ShimadzuXRD-6000 diffractometer.

[0059]FIG. 2

[0060] Diffractogram of Form VI atorvastatin carried out on ShimadzuXRD-6000 diffractometer.

[0061]FIG. 3

[0062] Diffractogram of Form VII atorvastatin carried out on ShimadzuXRD-6000 diffractometer.

[0063]FIG. 4

[0064] Diffractogram of Form VIII atorvastatin carried out on ShimadzuXRD-6000 diffractometer.

[0065]FIG. 5

[0066] Diffractogram of Form IX atorvastatin carried out on ShimadzuXRD-6000 diffractometer.

[0067]FIG. 6

[0068] Diffractogram of Form X atorvastatin carried out on ShimadzuXRD-6000 diffractometer.

[0069]FIG. 7

[0070] Diffractogram of Form XI atorvastatin carried out on ShimadzuXRD-6000 diffractometer.

[0071]FIG. 8

[0072] Diffractogram of Form XII atorvastatin carried out on ShimadzuXRD-6000 diffractometer.

[0073]FIG. 9

[0074] Diffractogram of Form XIII atorvastatin carried out on ShimadzuXRD-6000 diffractometer.

[0075]FIG. 10

[0076] Diffractogram of Form XIV atorvastatin carried out on Bruker D5000 diffractometer.

[0077]FIG. 11

[0078] Diffractogram of Form XV atorvastatin carried out on Bruker D5000 diffractometer.

[0079]FIG. 12

[0080] Diffractogram of Form XVI atorvastatin carried out on Bruker D5000 diffractometer.

[0081]FIG. 13

[0082] Diffractogram of Form XVII atorvastatin carried out on Bruker D5000 diffractometer.

[0083]FIG. 14

[0084] Diffractogram of Form XVIII atorvastatin carried out on Bruker D5000 diffractometer.

[0085]FIG. 15

[0086] Diffractogram of Form XIX atorvastatin carried out on Bruker D5000 diffractometer.

[0087]FIG. 16

[0088] Diffractogram of Form V atorvastatin carried out on Inel XRG-3000diffractometer.

[0089]FIG. 17

[0090] Diffractogram of Form VI atorvastatin carried out on InelXRG-3000 diffractometer.

[0091]FIG. 18

[0092] Diffractogram of Form VII atorvastatin carried out on InelXRG-3000 diffractometer.

[0093]FIG. 19

[0094] Diffractogram of Form VIII atorvastatin carried out on InelXRG-3000 diffractometer.

[0095]FIG. 20

[0096] Diffractogram of Form IX atorvastatin carried out on InelXRG-3000 diffractometer.

[0097]FIG. 21

[0098] Diffractogram of Form X atorvastatin carried out on Inel XRG-3000diffractometer.

[0099]FIG. 22

[0100] Diffractogram of Form XII atorvastatin carried out on InelXRG-3000 diffractometer.

[0101]FIG. 23

[0102] Diffractogram of Form XVI atorvastatin carried out on InelXRG-3000 diffractometer.

[0103]FIG. 24

[0104] Diffractogram of Form XVIII atorvastatin carried out on InelXRG-3000 diffractometer.

[0105]FIG. 25

[0106] Solid-state ¹³C nuclear magnetic resonance spectrum with spinningside bands identified by an asterisk of Form V atorvastatin.

[0107]FIG. 26

[0108] Solid-state ¹³C nuclear magnetic resonance spectrum with spinningside bands identified by an asterisk of Form VI atorvastatin.

[0109]FIG. 27

[0110] Solid-state ¹³C nuclear magnetic resonance spectrum with spinningside bands identified by an asterisk of Form VII atorvastatin.

[0111]FIG. 28

[0112] Solid-state ¹³C nuclear magnetic resonance spectrum with spinningside bands identified by an asterisk of Form VIII atorvastatin.

[0113]FIG. 29

[0114] Solid-state ¹³C nuclear magnetic resonance spectrum of Form Xatorvastatin.

[0115]FIG. 30

[0116] Raman spectrum of Form V.

[0117]FIG. 31

[0118] Raman spectrum of Form VI.

[0119]FIG. 32

[0120] Raman spectrum of Form VII.

[0121]FIG. 33

[0122] Raman spectrum of Form VIII.

[0123]FIG. 34

[0124] Raman spectrum of Form X.

[0125]FIG. 35 Raman spectrum of Form XII.

DETAILED DESCRIPTION OF THE INVENTION

[0126] Crystalline Form V, Form VI, Form VII, Form VIII, Form IX, FormX, Form XI, Form XII, Form XIII, Form XIV, Form XV, Form XVI, Form XVII,Form XVIII, and Form XIX atorvastatin may be characterized by theirX-ray powder diffraction patterns, by their solid state nuclear magneticresonance spectra (NMR), and/or their Raman spectra.

X-Ray Powder Diffraction

[0127] Forms V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII,XVIII, and XIX

[0128] Forms V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII,XVIII, or XIX atorvastatin were characterized by their X-ray powderdiffraction pattern. Thus, the X-ray diffraction patterns of Forms V,VI, VII, VIII, IX, X, XI, XII, or Form XIII atorvastatin were carriedout on a Shimadzu XRD-6000 X-ray powder diffractometer using CuK_(α)radiation. The instrument is equipped with a fine-focus X-ray tube. Thetube voltage and amperage were set at 40 kV and 40 mA, respectively. Thedivergence and scattering slits were set at 1°, and the receiving slitwas set at 0.15 mm. Diffracted radiation was detected by a NaIscintillation detector. A theta-two theta continuous scan at 3°/min (0.4sec/0.02° step) from 2.5 to 40° 2θ was used. A silicon standard wasanalyzed each day to check the instrument alignment. The X-raydiffraction patterns of Forms XIV, XV, XVI, XVII, XVIII, and XIX werecarried out on a Bruker D5000 diffractometer using copper radiation,fixed slits (1.0, 1.0, 0.6 mm), and a Kevex solid state detector. Datawas collected from 3.0 to 40.0 degrees in 2θ using a step size of 0.04degrees and a step time of 1.0 seconds. It should be noted that BrukerInstruments purchased Siemans; thus, a Bruker D 5000 instrument isessentially the same as a Siemans D 5000.

[0129] The X-ray diffraction patterns of Forms V, VI, VII, VIII, IX, X,XII, XVI, and XVIII were also carried out on an Inel diffractometer.X-ray diffraction analyses were carried out on an Inel XRG-3000diffractometer, equipped with a Curved Position Sensitive (CPS) detectorwith a 2θ range of 120 degrees. Real time data were collected usingCuK_(α) radiation starting at approximately 4°2θ at a resolution of0.03°2θ. The tube voltage and amperage were set to 40 kV and 30 mA,respectively. Samples were prepared for analysis by packing them intothin-walled glass capillaries. Each capillary was mounted onto agoniometer head that is motorized to permit spinning of the capillaryduring data acquisition. Instrument calibration was performed dailyusing a silicon reference standard. The Inel diffractograms for theavailable forms are shown in the figures without baseline subtraction.Calculating the intensities from these diffractograms is within theskill of the art and involves using baseline subtraction to account forbackground scattering (e.g., scattering from the capillary).

[0130] To perform an X-ray powder diffraction measurement on a Shimadzuor Bruker instrument like the ones used for measurements reportedherein, the sample is typically placed into a holder which has a cavity.The sample powder is pressed by a glass slide or equivalent to ensure arandom surface and proper sample height. The sample holder is thenplaced into the instrument (Shimadzu or Bruker). The source of the X-raybeam is positioned over the sample, initially at a small angle relativeto the plane of the holder, and moved through an arc that continuouslyincreases the angle between the incident beam and the plane of theholder. Measurement differences associated with such X-ray powderanalyses result from a variety of factors including: (a) errors insample preparation (e.g., sample height), (b) instrument errors (e.g.,flat sample errors), (c) calibration errors, (d) operator errors(including those errors present when determining the peak locations),and (e) preferred orientation. Calibration errors and sample heighterrors often result in a shift of all the peaks in the same directionand by the same amount. Small differences in sample height on a flatholder lead to large displacements in XRPD peak positions. A systematicstudy showed that, using a Shimadzu XRD-6000 in the typicalBragg-Brentano configuration, sample height differences of 1 mm led topeak shifts as high as 1°2θ (Chen, et al., J. Pharmaceutical andBiomedical Analysis, 2001;26:63). These shifts can be identified fromthe X-ray diffractogram and can be eliminated by compensating for theshift (applying a systematic correction factor to all peak positionvalues) or recalibrating the instrument. In contrast, the Inelinstrument used herein places the sample in a capillary which ispositioned at the center of the instrument. This minimizes sample heighterrors (a) and preferred orientation (e). Since, when using capillaries,the sample height is not established manually, the peak locations fromthe Inel measurements are typically more accurate than those from theShimadzu or the Bruker instrument. As mentioned above, it is possible torectify measurements from the various machines by applying a systematiccorrection factor to bring the peak positions into agreement. Ingeneral, this correction factor will bring the peak positions from theShimadzu and Bruker into agreement with the Inel and will be in therange of 0 to 0.2°2θ.

[0131] Table 1 lists the 2θ and relative intensities of all lines in thesample with a relative intensity of >10% for crystalline Forms V-XIXatorvastatin. The numbers listed in this table are rounded numbers.TABLE 1 Intensities and Peak Locations of All Diffraction Lines WithRelative Intensity Greater Than 10%^(a) for Forms V to XIX (Measured onShimadzu Diffractometer) Relative Relative Relative Relative RelativeIntensity Intensity Intensity Intensity Intensity 2θ (>10%) 2θ (>10%) 2θ(>10%) 2θ (>10%) 2θ (>10%) Form V Form VI Form VII Form VIII Form IX4.9* 9 7.2 11 8.6 76 7.5 61 8.8 50 6.0 15 8.3 77 10.2 70 9.2 29 9.4* 327.0 100 11.0 20 12.4* 12 10.0 16 11.2-11.7* 26 8.0* 20 12.4 11 12.8* 1512.1 10 16.7 59 8.6 57 13.8 9 17.6 20 12.8 6 17.5* 33 9.9 22 16.8 1418.3* 43 13.8 4 19.3* 55 16.6 42 18.5 100 19.3 100 15.1 13 21.4* 10019.0 27 19.7* 22 22.2* 14 16.7* 64 22.4* 33 21.1 35 20.9 14 23.4* 2318.6* 100 23.2* 63 25.0* 15 23.8* 26 20.3* 79 29.0* 15 25.5* 16 21.2 2421.9 30 22.4 19 25.8 33 26.5 20 27.4* 38 30.5 20 Form X Form XI Form XIIForm XIII Form XIV 4.7 35 10.8* 58 5.4 11 8.4 100 5.4 41 5.2 24 12.0 127.7 24 8.9 82 6.7 31 5.8 11 13.5 11 8.0 25 15.7* 45 7.7 100 6.9 13 16.552 8.6 42 16.4* 46 8.1 35 7.9 53 17.6-18.0* 35 8.9 25 17.6* 57 9.0 659.2 56 19.7 82 9.9 36 18.1* 62 16.5* 15 9.5 50 22.3 100 10.4* 24 19.7*58 17.6* 17 10.3* 13 23.2 26 12.5 18 20.8* 91 18.0-18.7* 21 11.8 20 24.428 13.9* 9 23.8* 57 19.5* 18 16.1 13 25.8 17 16.2 10 16.9 39 26.5 3017.8 70 19.1 100 27.3 31 19.8 71 28.7 19 19.4 100 21.4 49 29.5 12 20.851 22.3* 36 30.9* 17 21.7 13 23.7* 37 32.8* 11 22.4-22.6* 18 24.4 1533.6* 15 24.3 19 28.7 31 36.0* 15 25.5 24 38.5* 14 26.2 11 27.1 8 FormXV Form XVI Form XVII Form XVIII Form XIX 5.7 26 5.2 37 5.0 27 8.0 1005.2 32 6.1 21 6.4 34 6.1 33 9.2* 52 6.3 28 6.8 18 7.5 100 7.3 100 9.7*40 7.0 100 7.5 39 8.7 79 7.9 30 12.1 24 8.6 74 8.1 39 10.5* 19 8.5 2916.6* 48 10.5 34 8.5 42 12.0* 10 9.1 22 18.5 67 11.6* 26 9.5 33 12.7* 1710.0 45 12.7* 35 10.5* 18 16.7 26 12.1* 24 14.0 15 19.1-19.6* 32 18.3*27 14.8 17 16.7* 30 19.5 23 16.0-16.5* 20 18.9 86 20.1-20.4* 37 17.5* 2820.8 94 21.2-21.9* 32 19.0* 46 23.6* 38 22.9-23.3* 38 19.5 65 25.5* 3224.4-25.0* 35 20.2* 47 21.3 64 21.6 55 22.0 45

[0132] Because only 19 crystalline forms of atorvastatin are known, eachform can be identified and distinguished from the other crystallineforms by either a combination of lines or a pattern that is differentfrom the X-ray powder diffraction of the other forms.

[0133] For example, Table 2 lists combination of 2θ peaks for Forms V toXIX atorvastatin, i.e., a set of X-ray diffraction lines that are uniqueto each form. Forms I to IV atorvastatin disclosed in U.S. Pat. Nos.5,969,156 and 6,121,461 are included for comparison. TABLE 2 Forms I toXIX Unique Combination of 2θ Peaks Form I Form II Form III Form IV FormV Form VI Form VII Form VIII Form IX Form X 9.0 8.5 8.3 4.7 6.0 7.2 8.67.5 8.8 4.7 9.3 9.0 16.4 5.2 7.0 8.3 10.2 9.2 9.4* 6.9 10.1 17.1-17.419.9 7.7 8.0* 11.0 12.8* 10.0 16.7 7.9 10.4 20.5 24.2 9.4 9.9 18.5 17.616.7* 17.5* 9.2 11.7 10.1 16.6 18.3* 18.6* 19.3* 9.5 12.0 19.3 20.3*21.4* 19.1 16.8 29.0* 19.8 30.0 Form XI Form XII Form XIII Form XIV FormXV Form XVI Form XVII Form XVIII Form XIX 10.8* 7.7 8.4 5.4 5.7 5.2 6.18.0 5.5 16.5 8.0 8.9 6.7 6.1 6.4 7.3 9.2* 7.0 19.7 8.6 20.8* 7.7 7.5 7.57.9 16.6* 8.6 22.3 8.9 23.8* 8.1 8.1 8.7 10.0 18.5 10.5 9.9 9.0 8.5 16.719.0* 12.7* 17.8 9.5 20.1-20.4* 19.5 18.9 19.4 19.1-19.6* 22.9-23.3*21.3 20.8 21.6

Solid State Nuclear Magnetic Resonance (NMR)

[0134] Methodology

[0135] Solid-state ¹³C NMR spectra were obtained at 270 or 360 MHzTecmag instruments. High-power proton decoupling and cross-polarizationwith magic-angle spinning at approximately 4.7 and 4.2 kHz or 4.6 and4.0 kHz were used for 68 MHz (¹³C frequency) data acquisition, 4.9 and4.4 kHz were used for 91 MHz (¹³C frequency) data acquisition. The magicangle was adjusted using the Br signal of KBr by detecting the sidebands. A sample was packed into a 7 mm Doty rotor and used for eachexperiment. The chemical shifts were referenced externally to adamantineexcept for Form X where the chemical shifts are arbitrary.

[0136] Table 3 shows the solid-state NMR spectrum for crystalline FormsV, VI, VII, VIII, and X atorvastatin.

TABLE 3 Chemical Shifts for Forms V, VI, VII, VIII, and X AtorvastatinChemical Shift V VI VII VIII X 185.7 186.5 186.1 187.0 183.3 179.5 176.8176.5 176.8 179.5 166.9 168.2 166.5 167.9 165.5 163.1 161.0 159.8 159.2159.4 138.7 136.8 137.6 139.4 137.9 136.3 132.9 134.8 133.0 129.4 128.4127.8 128.3 128.7 127.9 124.7 123.2 122.0 122.3 122.3 121.8 118.8 119.2119.9 117.0 116.3 116.6 113.7 88.2 74.5 79.3 70.5 70.3 71.1 68.0 68.367.0 66.2 43.1 43.3 43.5 43.3 43.7 40.3 36.9 40.9 31.9 25.6 25.9 26.326.7 26.4 24.9 24.7 25.3 22.5 20.2 20.9 20.3 19.9 20.1 18.3

[0137] Table 4 shows unique solid-state NMR peaks for Forms V, VI, VII,VIII and X atorvastatin, ie, peaks within ±1.0 ppm. Forms I to IVatorvastatin are included for comparison. TABLE 4 Forms I to VIII and XUnique Solid-State NMR Peaks Form I Form II Form III Form IV Form V FormVI Form VII Form VIII Form X 182.8 181.0 161.0 181.4 176.8 163.1 183.3132.9 18.3 131.1 163.0 140.1 63.5 36.9 176.8 73.1 161.0 131.8 17.9 31.974.5 64.9 140.5 69.8 35.4

Raman Spectroscopy

[0138] Methodology

[0139] The Raman spectrum was obtained on a Raman accessory interfacedto a Nicolet Magna 860 Fourier transform infrared spectrometer. Theaccessory utilizes an excitation wavelength of 1064 nm and approximately0.45 W of neodymium-doped yttrium aluminum garnet (Nd:YAG) laser power.The spectrum represents 64 or 128 co-added scans acquired at 4 cm⁻¹resolution. The sample was prepared for analysis by placing a portioninto a 5-mm diameter glass tube and positioning this tube in thespectrometer. The spectrometer was calibrated (wavelength) with sulfurand cyclohexane at the time of use.

[0140] Table 5 shows the Raman spectra for Forms V, VI, VII, VIII, X,and XII atorvastatin. TABLE 5 Raman Peak Listing for Forms V, VI, VII,VIII, X and XII Atorvastatin Form V Form VI Form VII Form VIII Form XForm XII 3062 3058 3060 3065 3062 3064 2973 2935 2927 2923 2911 29261652 1651 1649 1658 1650 1652 1604 1603 1603 1603 1603 1603 1528 15561524 1531 1525 1527 1525 1510 1481 1478 1478 1476 1478 1470 1440 14131412 1412 1413 1411 1410 1397 1397 1368 1368 1369 1367 1240 1240 11581157 1159 1158 1159 1034 1034 1034 1034 1001 997 998 997 999 1002 825824 824 823 245 224 130 114 121 116

[0141] Table 6 lists unique Raman peaks for Forms V, VI, VII, VIII, X,and XII atorvastatin, ie, only one other form has a peak with ±4 cm⁻¹.In the case of Forms VI and X, it is a unique combination of peaks.Forms I to IV atorvastatin are included for comparison. TABLE 6 Forms Ito VIII, X and XII Unique Raman Peaks Form I Form II Form III Form IVForm V Form VI* Form VII Form VIII Form X* Form XII 3080 1663 2938 4231440 3058 1397 1510 3062 2973 1512 359 1660 215 1397 2935 1481 2911 14391510 132 130 1556 1413 1525 142 1481 1525 121 1240 1427 1182 859

[0142] Crystalline Forms V to XIX atorvastatin of the present inventionmay exist in anhydrous forms as well as hydrated and solvated forms. Ingeneral, the hydrated forms are equivalent to unhydrated forms and areintended to be encompassed within the scope of the present invention.Crystalline Form XIV contains about 6 mol of water. Preferably, Form XIVcontains 6 mol of water. Crystalline Forms V, X, and XV atorvastatincontain about 3 mol of water. Preferably, Forms V, X, and XVatorvastatin contain 3 mol of water.

[0143] Crystalline Form VII contains about 1.5 mol of water. Preferably,Form VII atorvastatin contains 1.5 mol of water. Crystalline Form VIIIcontains about 2 mol of water. Preferably, Form VIII atorvastatincontains 2 mol of water.

[0144] Crystalline Forms XVI-XIX may exist as a solvate.

[0145] Crystalline forms of atorvastatin of the present invention,regardless of the extent of hydration and/or solvation having equivalentx-ray powder diffractograms, ssNMR, or Raman spectra are within thescope of the present invention.

[0146] Crystalline forms, in general, can have advantageous properties.A polymorph, solvate, or hydrate is defined by its crystal structure andproperties. The crystal structure can be obtained from X-ray data orapproximated from other data. The properties are determined by testing.The chemical formula and chemical structure does not describe or suggestthe crystal structure of any particular polymorphic or crystallinehydrate form. One cannot ascertain any particular crystalline form fromthe chemical formula, nor does the chemical formula tell one how toidentify any particular crystalline solid form or describe itsproperties. Whereas a chemical compound can exist in three states—solid,solution, and gas-crystalline solid forms exist only in the solid state.Once a chemical compound is dissolved or melted, the crystalline solidform is destroyed and no longer exists (Wells J. I., Aulton M. E.Pharmaceutics. The ‘Science of Dosage Form Design. Reformulation, AultonM. E. ed., Churchill Livingstone, 1988;13:237).

[0147] The new crystalline forms of atorvastatin described herein haveadvantageous properties. Form VII has good chemical stability, which iscomparable to Form I (disclosed in U.S. Pat. No. 5,969,156). Sincenoncrystalline forms of atorvastatin are not chemically stable, this isa significant advantage, which would translate into enhanced shelf lifeand longer expiration dating. Form VII can be prepared fromacetone/water, whereas Form I is prepared from the more toxicmethanol/water system. Form VII is the sesquihydrate and contains lesswater, meaning that a unit weight of Form VII contains more atorvastatinmolecules, meaning it is of higher potency.

[0148] The ability of a material to form good tablets at commercialscale depends upon a variety of drug physical properties, such as theTableting Indices described in Hiestand H. and Smith D., Indices ofTableting Performance, Powder Technology, 1984;38:145-159. These indicesmay be used to identify forms of atorvastatin calcium which havesuperior tableting performance. One such index is the Brittle FractureIndex (BFI), which reflects brittleness, and ranges from 0 (good—lowbrittleness) to 1 (poor—high brittleness). For example, Form VII has aBFI value 0.09, while Form I has a BFI value 0.81. Thus, Form VII isless brittle than Form I. This lower brittleness indicates greater easeof manufacture of tablets.+

[0149] Form VIII also has less water than Form I (dihydrate vstrihydrate) and thus a gram of Form VIII contains more atorvastatinmolecules.

[0150] Form X is advantageous in that it can be prepared from the lesstoxic isopropanol (IPA):water system, thus avoiding the more toxicmethanol:water system.

[0151] Form XII has the highest melting point (210.6). Since highmelting point correlates with stability at high temperature, this meansthis form is most stable at temperatures near the melting point. Highmelting forms can be advantageous when process methods involving hightemperatures are used. Form XII is also prepared from the less toxictetrahydrofuran (THF) water system.

[0152] Form XIV is prepared using the less toxic THF/water system.

[0153] The present invention provides a process for the preparation ofcrystalline Forms V to XIX atorvastatin which comprises crystallizingatorvastatin from a solution in solvents under conditions which yieldcrystalline Forms V to XIX atorvastatin.

[0154] The precise conditions under which crystalline Forms V to XIXatorvastatin are formed may be empirically determined, and it is onlypossible to give a number of methods which have been found to besuitable in practice.

[0155] The compounds of the present invention can be prepared andadministered in a wide variety of oral and parenteral dosage forms.Thus, the compounds of the present invention can be administered byinjection, that is, intravenously, intramuscularly, intracutaneously,subcutaneously, intraduodenally, or intraperitoneally. Also, thecompounds of the present invention can be administered by inhalation,for example, intranasally. Additionally, the compounds of the presentinvention can be administered transdermally. It will be obvious to thoseskilled in the art that the following dosage forms may comprise as theactive component, either compounds or a corresponding pharmaceuticallyacceptable salt of a compound of the present invention.

[0156] For preparing pharmaceutical compositions from the compounds ofthe present invention, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, pills, capsules, cachets, suppositories, and dispersiblegranules. A solid carrier can be one or more substances which may alsoact as diluents, flavoring agents, solubilizers, lubricants, suspendingagents, binders, preservatives, tablet disintegrating agents, or anencapsulating material.

[0157] In powders, the carrier is a finely divided solid which is in amixture with the finely divided active component.

[0158] In tablets, the active component is mixed with the carrier havingthe necessary binding properties in suitable proportions and compactedin the shape and size desired.

[0159] The powders and tablets preferably contain from two or ten toabout seventy percent of the active compound. Suitable carriers aremagnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin,dextrin, starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component, with or without other carriers,is surrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

[0160] For preparing suppositories, a low melting wax, such as a mixtureof fatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

[0161] Liquid form preparations include solutions, suspensions,retention enemas, and emulsions, for example water or water propyleneglycol solutions. For parenteral injection, liquid preparations can beformulated in solution in aqueous polyethylene glycol solution.

[0162] Aqueous solutions suitable for oral use can be prepared bydissolving the active component in water and adding suitable colorants,flavors, stabilizing, and thickening agents as desired.

[0163] Aqueous suspensions suitable for oral use can be made bydispersing the finely divided active component in water with viscousmaterial, such as natural or synthetic gums, resins, methylcellulose,sodium carboxymethylcellulose, and other well-known suspending agents.

[0164] Also included are solid form preparations which are intended tobe converted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

[0165] The pharmaceutical preparation is preferably in unit dosage form.In such form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

[0166] The quantity of active component in a unit dose preparation maybe varied or adjusted from 0.5 mg to 100 mg, preferably 2.5 mg to 80 mgaccording to the particular application and the potency of the activecomponent. The composition can, if desired, also contain othercompatible therapeutic agents.

[0167] In therapeutic use as hypolipidemic and/or hypocholesterolemicagents and agents to treat osteoporosis and Alzheimer's disease, thecrystalline Forms V to XIX atorvastatin utilized in the pharmaceuticalmethod of this invention are administered at the initial dosage of about2.5 mg to about 80 mg daily. A daily dose range of about 2.5 mg to about20 mg is preferred. The dosages, however, may be varied depending uponthe requirements of the patient, the severity of the condition beingtreated, and the compound being employed. Determination of the properdosage for a particular situation is within the skill of the art.Generally, treatment is initiated with smaller dosages which are lessthan the optimum dose of the compound. Thereafter, the dosage isincreased by small increments until the optimum effect under thecircumstance is reached. For convenience, the total daily dosage may bedivided and administered in portions during the day if desired.

[0168] The following nonlimiting examples illustrate the inventors'preferred methods for preparing the compounds of the invention.

EXAMPLE 1

[0169][R-(R*,R*)]-2-(4-Fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid hemi calcium salt (Forms V-XIX atorvastatin)

[0170] Form V Atorvastatin

[0171] Method A

[0172] Amorphous atorvastatin calcium (U.S. Pat. No. 5,273,995) wasslurried in a mixture of acetonitrile/water (9:1) to afford crystallineForm V atorvastatin.

[0173] Method B

[0174] Crystalline Form I atorvastatin calcium (U.S. Pat. No. 5,969,156)was slurried in a mixture of acetonitrile/water (9:1) at 60° C.overnight, filtered, and air dried to afford crystalline Form Vatorvastatin.

[0175] Method C

[0176] Amorphous atorvastatin calcium (U.S. Pat. No. 5,273,995) wasstressed under vapors of acetonitrile/water (9:1) to afford crystallineForm V atorvastatin.

[0177] Method D

[0178] Acetonitrile was added to a solution of amorphous atorvastatincalcium (U.S. Pat. No. 5,273,995) in tetrahydrofuran/water (9:1) andcooled to afford crystalline Form V atorvastatin.

[0179] Method E

[0180] Acetonitrile was added to a solution of amorphous atorvastatincalcium (U.S. Pat. No. 5,273,995) in dimethylformamide/water and fastevaporation affords crystalline Form V atorvastatin.

[0181] Method F

[0182] Amorphous atorvastatin calcium (U.S. Pat. No. 5,273,995) diffusedin a vapor of acetonitrile/water (9:1) to afford crystalline Form Vatorvastatin.

[0183] Crystalline Form V atorvastatin, mp 171.4° C., trihydrate

[0184] Karl Fischer 4.88% (3 mol of water).

[0185] Form VI Atorvastatin

[0186] Method A

[0187] Amorphous atorvastatin calcium (U.S. Pat. No. 5,273,995) wasplaced into a vapor jar containing dimethylformamide/water (9:1) for 20days to afford crystalline Form VI atorvastatin.

[0188] Method B

[0189] Fast evaporation of a dimethylformamide/water solution ofamorphous atorvastatin calcium (U.S. Pat. No. 5,273,995) affordedcrystalline Form VI atorvastatin.

[0190] Method C

[0191] Fast evaporation of a dimethylformamide/water (saturated)solution of amorphous atorvastatin calcium (U.S. Pat. No. 5,273,995)seeded with crystalline Form VI afforded crystalline Form VIatorvastatin.

[0192] Crystalline Form VI atorvastatin, mp 145.9° C.

[0193] Form VII Atorvastatin

[0194] Method A

[0195] A solution of amorphous atorvastatin calcium (U.S. Pat. No.5,273,995) in acetone/water (1:1) (5.8 mg/mL) was stirred overnight. Asolid formed which was filtered to afford crystalline Form VIIatorvastatin.

[0196] Method B

[0197] A solution of amorphous atorvastatin calcium (U.S. Pat. No.5,273,995) in acetone/water (1:1) was evaporated at 50° C. to affordcrystalline Form VII atorvastatin.

[0198] Method C

[0199] A saturated solution of amorphous atorvastatin calcium (U.S. Pat.No. 5,273,995) in acetone/water (1:1) was seeded with crystalline FormVII atorvastatin to afford crystalline Form VII atorvastatin.

[0200] Method D

[0201] Fast evaporation of a saturated solution of amorphousatorvastatin calcium (U.S. Pat. No. 5,273,995) in acetone/water (1:1)was seeded with crystalline Form VII to afford crystalline Form VIIatorvastatin.

[0202] Crystalline Form VII atorvastatin, mp 195.9° C., 1.5 hydrate

[0203] Karl Fischer 2.34% (1.5 mol of water).

[0204] Form VIII Atorvastatin

[0205] Method A

[0206] A solution of amorphous atorvastatin calcium (U.S. Pat. No.5,273,995) in dimethylformamide/water (saturated) (9:1), was seeded withcrystalline Form VII and evaporated to afford crystalline Form VIIIatorvastatin.

[0207] Method B

[0208] Fast evaporation of a solution of amorphous atorvastatin calcium(U.S. Pat. No. 5,273,995) in dimethylformamide/water (9:1) affordscrystalline Form VIII atorvastatin.

[0209] Crystalline Form VIII atorvastatin, mp 151° C., dihydrate

[0210] Karl Fischer 2.98% (2 mol of water).

[0211] Form IX Atorvastatin

[0212] Method A

[0213] A solution of amorphous atorvastatin calcium (U.S. Pat. No.5,273,995) in acetone/water (6:4) (3.4 mg/mL) was evaporated on a rotaryevaporator to afford crystalline Form IX atorvastatin.

[0214] Method B

[0215] A solution of amorphous atorvastatin calcium (U.S. Pat. No.5,273,995) in acetone/water (6:4) was filtered, seeded with crystallineForm IX evaporated on a rotary evaporator to afford crystalline Form IXatorvastatin.

[0216] Method C

[0217] A solution of amorphous atorvastatin calcium (U.S. Pat. No.5,273,995) in acetone/water (6:4) was stirred for 0.5 hours, filtered,evaporated on rotary evaporator to concentrate the solution, and driedin a vacuum oven to afford crystalline Form IX atorvastatin.

[0218] Form X Atorvastatin

[0219] Method A

[0220] A slurry of amorphous atorvastatin calcium (U.S. Pat. No.5,273,995) in isopropanol/water (9:1) was stirred for a few days,filtered, and air dried to afford crystalline Form X atorvastatin.

[0221] Method B

[0222] A slurry of amorphous atorvastatin calcium (U.S. Pat. No.5,273,995) in isopropanol/water (9:1) was stirred for 5 days, filtered,and air dried to afford crystalline Form X atorvastatin.

[0223] Method C

[0224] A saturated solution of amorphous atorvastatin calcium (U.S. Pat.No. 5,273,995) in isopropanol/water (9:1) was stirred for 2 days,filtered, and air dried to afford crystalline Form X atorvastatin.

[0225] Crystalline Form X atorvastatin, mp 180.1° C., trihydrate

[0226] Karl Fischer 5.5% (3.5 mol of water).

[0227] Form XI Atorvastatin

[0228] A solution of amorphous atorvastatin calcium (U.S. Pat. No.5,273,995) in acetonitrile/water (9:1) was filtered and allowed toevaporate slowly to afford crystalline Form XI atorvastatin.

[0229] Form XII Atorvastatin

[0230] Crystalline Form I atorvastatin calcium (U.S. Pat. No. 5,969,156)was slurried in tetrahydrofuran/water (2:8) at 90° C. for 5 days,filtered, and air dried to afford crystalline Form XII atorvastatin.

[0231] Crystalline Form XII atorvastatin, mp 210.6° C.

[0232] Form XIII Atorvastatin

[0233] Crystalline Form I atorvastatin calcium (U.S. Pat. No. 5,969,156)was added to 10 mL 2:8 water:methanol to leave a layer of solid on thebottom of a vial. The slurry was heated to about 70° C. for 5 days. Thesupernatant was removed, and the solid air dried to afford crystallineForm XIII atorvastatin.

[0234] Form XIV Atorvastatin

[0235] Amorphous atorvastatin calcium (U.S. Pat. No. 5,273,995), 1 g,was slurried for 3 weeks in 45 mL of isopropyl alcohol/5 mL of water(9:1) at ambient temperature. The mixture was filtered to affordcrystalline Form XIV atorvastatin after drying at ambient temperature.

[0236] Differential scanning calorimetry (DSC) indicates a lowdesolvation event at about 60° C. (peak) followed by a melt at about150° C. Combustion analysis indicates that the compound is ahexahydrate. Thermographic infrared spectroscopy (TG-1R) shows thecompound contains water. Karl Fischer shows the compound contains 5.8%water.

[0237] Form XV Atorvastatin

[0238] Amorphous atorvastatin calcium (U.S. Pat. No. 5,273,995), 1 g,was slurried for 3 weeks in 45 mL acetonitrile/5 mL of water (9:1) atambient temperature. The mixture was filtered to afford crystalline FormXV atorvastatin after drying at ambient temperature. DSC indicates a lowdesolvation event at about 78° C. (peak) followed by a melt at about165° C. Combustion analysis indicates that the compound is a trihydrate.TG-IR shows the compound contains water.

[0239] Form XVI Atorvastatin

[0240] Amorphous atorvastatin calcium (U.S. Pat. No. 5,273,995), 1 g,was slurried for about 1 day in 9:1 acetonitrile/water at roomtemperature. The mixture was filtered to afford crystalline Form XVIatorvastatin after drying at ambient temperature. DSC indicates a broadendotherm at peak temperature of 72° C. and an endotherm with onsettemperature of 164° C. The weight loss profile by thermographic analysis(TGA) indicates a total weight loss of about 7% at 30° C. to 160° C.Combustion analysis indicates that TGA and Karl Fischer analysis (shows7.1% water) indicates the compound is a tetrahydrate/acetonitrilesolvate.

[0241] Form XVII Atorvastatin

[0242] Amorphous atorvastatin calcium (U.S. Pat. No. 5,273,995), 0.5 g,was slurried for about 2 days in 5 mL of 9:1 dimethylformamide(DMF)/water containing 25 mL of acetonitrile at room temperature. Themixture was filtered to afford crystalline Form XVII atorvastatin afterdrying at ambient temperature. DSC showed multiple broad endothermsindicating the compound was a solvate.

[0243] Form XVIII Atorvastatin

[0244] Crystalline Form XVI atorvastatin, 0.5 g, was dried for about 1day at room temperature to afford crystalline Form XVIII atorvastatin.DSC showed a broad endotherm at low temperature indicating the compoundwas a solvate. Karl Fischer analysis showed the compound contained 4.4%water.

[0245] Form XIX Atorvastatin

[0246] Amorphous atorvastatin calcium (U.S. Pat. No. 5,273,995), 0.4 g,was slurried for about 7 days in 4 mL methyl ethyl ketone at roomtemperature. The mixture was filtered to afford crystalline Form XIXatorvastatin after drying at ambient temperature. DSC indicated a lowdesolvation event at about 50° C. (peak) followed by a melt at about125° C. TGA analysis indicates that the compound is a solvate thatdesolvates at low temperature.

What is claimed is:
 1. A crystalline Form V atorvastatin or a hydratethereof having an X-ray powder diffraction containing the following 2θvalues measured using CuK_(α) radiation: 4.9 (broad), 6.0, 7.0, 8.0(broad), 8.6, 9.9, 16.6, 19.0, and 21.1.
 2. A crystalline Form VIatorvastatin or a hydrate thereof having an X-ray powder diffractioncontaining the following 2θ values measured using CuK_(α) radiation:7.2, 8.3, 11.0, 12.4, 13.8, 16.8, 18.5, 19.7 (broad), 20.9, and 25.0. 3.A crystalline Form VII atorvastatin or a hydrate thereof having an X-raypowder diffraction containing the following 2θ values measured usingCuK_(α) radiation: 8.6, 10.2, 12.4 (broad), 12.8 (broad), 17.6, 18.3(broad), 19.3, 22.2 (broad), 23.4 (broad), 23.8 (broad), and 25.5(broad).
 4. A crystalline Form VIII atorvastatin or a hydrate thereofhaving an X-ray powder diffraction containing the following 2θ valuesmeasured using CuK_(α) radiation: 7.5, 9.2, 10.0, 12.1, 12.8, 13.8,15.1, 16.7 (broad), 18.6 (broad), 20.3 (broad), 21.2, 21.9, 22.4, 25.8,26.5, 27.4 (broad), and 30.5.
 5. A crystalline Form IX atorvastatin or ahydrate thereof having an X-ray powder diffraction containing thefollowing 2θ values measured using CuK_(α) radiation: 8.8, 9.4 (broad),11.2-11.7 (broad), 16.7, 17.5 (broad), 19.3 (broad), 21.4 (broad), 22.4(broad), 23.2 (broad), and 29.0 (broad).
 6. A crystalline Form Xatorvastatin or a hydrate thereof having an X-ray powder diffractioncontaining the following 2θ values measured using CuK_(α) radiation:4.7, 5.2, 5.8, 6.9, 7.9, 9.2, 9.5, 10.3 (broad), 11.8, 16.1, 16.9, 19.1,19.8, 21.4, 22.3 (broad), 23.7 (broad), 24.4, and 28.7.
 7. A crystallineForm XI atorvastatin or a hydrate thereof having an X-ray powderdiffraction containing the following 2θ values measured using CuK_(α)radiation: 10.8 (broad), 12.0, 13.5, 16.5, 17.6-18.0 (broad), 19.7,22.3, 23.2, 24.4, 25.8, 26.5, 27.3, 28.7, 29.5, 30.9 (broad), 32.8(broad), 33.6 (broad), 36.0 (broad), and 38.5 (broad).
 8. A crystallineForm XII atorvastatin or a hydrate thereof having an X-ray powderdiffraction containing the following 2θ values measured using CuK_(α)radiation: 5.4, 7.7, 8.0, 8.6, 8.9, 9.9, 10.4 (broad), 12.5, 13.9(broad), 16.2, 17.8, 19.4, 20.8, 21.7, 22.4-22.6 (broad), 24.3, 25.5,26.2, and 27.1.
 9. A crystalline Form XIII atorvastatin or a hydratethereof having an X-ray powder diffraction containing the following 2θvalues measured using CuK_(α) radiation: 8.4, 8.9, 15.7 (broad), 16.4(broad), 17.6 (broad), 18.1 (broad), 19.7 (broad), 20.8 (broad), and23.8 (broad).
 10. A crystalline Form XIV atorvastatin or a hydratethereof having an X-ray powder diffraction containing the following 2θvalues measured using CuK_(α) radiation: 5.4, 6.7, 7.7, 8.1, 9.0, 16.5(broad), 17.6 (broad), 18.0-18.7 (broad), and 19.5 (broad).
 11. Acrystalline Form XV atorvastatin or a hydrate thereof having an X-raypowder diffraction containing the following 2θ values measured usingCuK_(α) radiation: 5.7, 6.1, 6.8, 7.5, 8.1, 8.5, 9.5, 10.5 (broad), and19.1-19.6 (broad).
 12. A crystalline Form XVI atorvastatin or a hydratethereof having an X-ray powder diffraction containing the following 2θvalues measured using CuK_(α) radiation: 5.2, 6.4, 7.5, 8.7, 10.5(broad), 12.0 (broad), 12.7 (broad), 16.7, 18.3 (broad), 19.5, 20.1-20.4(broad), 21.2-21.9 (broad), 22.9-23.3 (broad), and 24.4-25.0 (broad).13. A crystalline Form XVII atorvastatin or a hydrate thereof having anX-ray powder diffraction containing the following 2θ values measuredusing CuK_(α) radiation: 5.0, 6.1, 7.3, 7.9, 8.5, 9.1, 10.0, 12.1(broad), 14.8, 16.0-16.5 (broad), 17.5 (broad), 19.0 (broad), 19.5, 20.2(broad), 21.3, 21.6, and 22.0.
 14. A crystalline Form XVIII atorvastatinor a hydrate thereof having an X-ray powder diffraction containing thefollowing 2θ values measured using CuK_(α) radiation: 8.0, 9.2 (broad),9.7 (broad), 12.1, 16.6 (broad), and 18.5.
 15. A crystalline Form XIXatorvastatin or a hydrate thereof having an X-ray powder diffractioncontaining the following 2θ values measured using CuK_(α) radiation:5.2, 6.3, 7.0, 8.6, 10.5, 11.6 (broad), 12.7 (broad), 14.0, 16.7(broad), 18.9, 20.8, 23.6 (broad), and 25.5 (broad).